There is now no doubt that cellular immune responses select for new mutant viruses. The two outstanding issues that remain are whether there is any functional significance associated with escape from these responses and furthermore, whether the selected escape mutants can be propagated in populations. The resolution of these two issues will be important in HIV vaccine design and pathogenesis studies. Recent HIV vaccine strategies have targeted cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) responses, which are associated with control of viral replication. However, immunodeficiency viruses evolve rapidly, spawning new mutant viruses If escape variant viruses are stable after transmission to new hosts, cellular immune responses could select for the accumulation of escape variation in populations, complicating AIDS vaccine development. We will examine the functional significance of escape from cellular immune responses and the propagation of these escape mutants in two cohorts of MHC-defined macaques. In Specific Aim I we will examine the functional significance and propagation of escape mutants in 3 immunodominant CTL epitopes. We have infected 52 macaques with SIVmac239 and have identified 3 rhesus macaques that control virus replication. Surprisingly all three of these macaques express both of the MHC class I molecules Mamu-A*01 and Mamu-B*17. Together, these two molecules bind peptides that elicit 3 high-frequency CTL responses. These three epitopes usually escape after infection. Infection of Mamu- A*01/Mamu-B*17-positive macaques with "pre-escaped" viruses should abrogate these immunodominant CTL responses, resulting in loss of ability to control viral replication. In Specific Aim II we will examine the functional significance and propagation of escape mutants in multiple CTL and HTL epitopes. We have identified 6 sibling pairs of MHC-identical rhesus macaques and we have infected one sibling of each pair with SIVmac239 Infection of the MHC-identical siblings with "pre-escaped" virus at all relevant CTL and HTL epitopes should cause rapid disease progression. Finally, we hypothesize that escaped virus evolving without any selective pressure on the "pre-escaped" CTL and HTL epitopes will evolve towards higher fitness viruses.